CD157: from Myeloid Cell Differentiation Marker to Therapeutic Target in Acute Myeloid Leukemia
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cells Review CD157: From Myeloid Cell Differentiation Marker to Therapeutic Target in Acute Myeloid Leukemia Yuliya Yakymiv 1, Stefania Augeri 1, Giulia Fissolo 1, Silvia Peola 1, Cristiano Bracci 1, Monica Binaschi 2, Daniela Bellarosa 2, Andrea Pellacani 3, Enza Ferrero 1, Erika Ortolan 1 and Ada Funaro 1,* 1 Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, 10126 Torino, Italy; [email protected] (Y.Y.); [email protected] (S.A.); giulia.fi[email protected] (G.F.); [email protected] (S.P.); [email protected] (C.B.); [email protected] (E.F.); [email protected] (E.O.) 2 Department of Experimental and Translational Oncology, Menarini Ricerche S.p.A, 00071 Pomezia, Rome, Italy; [email protected] (M.B.); [email protected] (D.B.) 3 Menarini Ricerche S.p.A, 50131 Florence, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-011-6705988 Received: 24 October 2019; Accepted: 4 December 2019; Published: 5 December 2019 Abstract: Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), CD157 proved not to be restricted to the myeloid compartment and to have a diversified functional repertoire ranging from immunity to cancer and metabolism. Despite being a NAD+-metabolizing ectoenzyme anchored to the cell surface through a glycosylphosphatidylinositol moiety, the functional significance of human CD157 as an enzyme remains unclear, while its receptor role emerged from its discovery and has been clearly delineated with the identification of its high affinity binding to fibronectin. The aim of this review is to provide an overview of the immunoregulatory functions of human CD157/BST-1 in physiological and pathological conditions. We then focus on CD157 expression in hematological tumors highlighting its emerging role in the interaction between acute myeloid leukemia and extracellular matrix proteins and its potential utility for monoclonal antibody targeted therapy in this disease. Keywords: CD157/BST-1; myeloid cells; stem cells; cyclic ADPR; cell adhesion; acute myeloid leukemia; therapeutic defucosylated monoclonal antibody; MEN1112/OBT357 1. Introduction CD157 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, discovered over three decades ago and originally designated as Mo5 myeloid cell differentiation marker [1]. Subsequently, in the VI Workshop on Leukocyte Differentiation Antigens, Mo5 and the molecule recognized by the RF3 anti-Bone Marrow Stromal Cell Antigen 1 (BST-1) monoclonal antibody were grouped together and designated as CD157 [2]. The human BST1 gene maps to chromosome 4p15.32, adjacent to its paralog CD38 with which it forms part of the ADP ribosyl cyclase (ARC) gene family [3]. Comparative gene analysis revealed a striking exon-intron structural similarity between BST1 and CD38, indicating that the two genes evolved by duplication from an ancestral gene before the divergence of humans and rodents [4]. Following duplication, the two genes went their separate ways and diverged in structure and sequence under the influence of mutation, selection and drift [3]. Human BST1 was cloned in 1994 and one BST1 transcript was identified which encoded the canonical CD157/BST-1 protein of 318 amino Cells 2019, 8, 1580; doi:10.3390/cells8121580 www.mdpi.com/journal/cells Cells 2019, 8, 1580 2 of 16 acids [5]. Recently, our laboratory described a second CD157/BST-1 transcript which encompasses an additional exon interposed between exons 1 and 2 of the BST1 gene (Figure1). This 10-exon transcript encodes a protein of 333 amino acids, named CD157-002. This serendipitous finding revealed that human CD157 is so far the only member of the ARC gene family regulated by alternative splicing. The two transcripts appear to be generally co-expressed, although the CD157-001 transcript is usually far more highly expressed [6]. Figure 1. Alternative splicing of human BST1. The revised structure of human BST1 consisting of 10 exons [6]. Skipping of exon 1b by alternative splicing yields the canonical CD157-001 isoform of 318 aa whereas inclusion of exon 1b adds 15 aa in-frame to the polypeptide, yielding the CD157-002 isoform of 333 aa. Human BST1 variants have been described with four single-nucleotide polymorphisms (SNPs) identified as risk factors for sporadic late-onset Parkinson’s disease (PD) in a Japanese GWA study [7], and in the Northern Han Chinese population [8,9], while this finding remains controversial in the European population [10,11]. Moreover, three possible risk SNPs for autism spectrum disorders (ASD) were identified in a Japanese population [12]. However, these variants were not found significantly associated with ASD or with the severity of the disease in the Han Chinese population [13]. It is conceivable that clinical and genetic heterogeneity of ASD and PD and the complexity of their inheritance patterns may justify variable distribution of these SNPs in different ethnic populations. Although the causal link between the BST1 SNP and brain diseases remains unclear, functional implications of CD157 in the pathophysiology of several neurologic disorders are supported by the observation of partially deleted BST1 and CD38 genes in an ASD patient [14] and by the impaired social behaviors associated with anxiety and depression occurring in Bst1 knockout mice [15]. Since CD157 is expressed in mouse brain, especially during embryonic development, it has been speculated that it might be involved in the processes of neuronal development that relates to neurologic disorders such as PD and ASD [16]. 2. CD157 Protein Structure and Tissue Distribution in Health and Disease The CD157 protein contains four predicted N-linked glycosylation sites in the extracellular region [17] facilitating the folding of the nascent polypeptide chain into a conformation fitting intracellular transport and enzymatic activity. The molecular weight of CD157 ranges between 42–50 kDa, according to its heterogeneous glycosylation patterns [18,19]. Dimeric forms of CD157 were detected when the protein was exogenously expressed at high epitope density in MCA102 and CHO fibroblasts [20]. In addition to the GPI-anchored form, a soluble form of CD157 is detected in serum and other biological fluids. Very high levels of soluble CD157 were reported in the sera of patients with rheumatoid arthritis compared to healthy controls [21]. Elevated soluble CD157 was also found in Cells 2019, 8, 1580 3 of 16 pleural effusions from patients with malignant pleural mesothelioma compared to patients with other cancer types or benign pathologies [22]. Recently, the concentration of soluble CD157 was found to be significantly increased in pleural fluid obtained from tuberculous pleurisy patients with respect to patients with pneumonia or lung cancer [23]. CD157 can be shed either as a soluble protein, generated by proteolytic cleavage of the membrane-bound form, or as an exosome-anchored protein. CD157 was found to be expressed by exosomes released by myeloid-derived suppressor cells [24] and by mesothelioma cells, both in vitro [25] and in vivo [22]. The functional role of soluble CD157 remains to be defined. As stated in the pioneering studies performed by Todd et al. in the 1980s, in the human hematopoietic system CD157 is prevalently expressed by cells of the myelomonocytic lineage [1,26]. In normal hematopoietic cells, CD157 is expressed at low levels throughout neutrophil maturation, its expression level progressively increasing at the later stages of maturation, from the promyelocytic stage onwards [27]. CD157 is also expressed in myeloid-derived suppressor cells, which expand during chronic and acute inflammatory conditions [28] and in patients with myeloid hematological malignancies [29]. CD157 is not expressed in early CD34+ monocytic precursors but it becomes clearly expressed in early stage of maturation characterized by low expression of CD36, and strongly expressed in the more mature CD36high monocytic cells [30] and in macrophages [31]. However, increasing evidence shows that CD157 actually has a broader pattern of expression than previously thought. Indeed, in addition to bone marrow stromal cells, vascular endothelium [5], and circulating endothelial cells [32], CD157 is expressed in several other cell types and tissues of both lymphoid and nonlymphoid origin [33]. The general picture that emerges from studies performed in humans and mice indicates that CD157 expression is not restricted to the myeloid compartment but extends to tissues of different origins, such as gut [34], lung [35], eye [36], blood vascular system [37], and brain [16]. Of note, its expression frequently marks cell stemness [38–40]. In hematological malignancies, low expression of CD157 was reported in the HL-60 acute promyelocytic leukemia cell line [41]; however, no data are available on the expression of CD157 in patients with this leukemia. CD157 expression in acute myeloid leukemia is described below (Section7). CD157 has been reported to play a role in disease progression in certain malignancies by regulating cell invasion and metastasis. Our group reported that CD157 is expressed in >90% of primary serous epithelial ovarian cancer [42] where high CD157 expression correlates with increased tumor aggressiveness [43], promotes epithelial-to-mesenchymal transition